Pharmaceutically active agents are generally formulated as solid or liquid dosage forms for administration. Such dosage forms generally comprise the active agent combined with excipients to form materials that may be conveniently and reliably administered to a patient in need of such therapy, and following administration, the active agent is absorbed and distributed in the patient in a way that leads to good efficacy and safety.
It is known that poorly water-soluble drugs may be formulated as nanoparticles. Nanoparticles are of interest for a variety of reasons, such as to improve the bioavailability of poorly water-soluble drugs, to provide targeted drug delivery to specific areas of the body, to reduce side effects, or to reduce variability in vivo.
A variety of approaches have been taken to formulate drugs as nanoparticles. One approach is to decrease the size of crystalline drug by grinding or milling the drug in the presence of a surface modifier. Another approach to forming nanoparticles is to precipitate the drug in the presence of a film forming material such as a polymer.
There remain a number of problems associated with the use of nanoparticles to deliver pharmaceutical compounds to the body. The nanoparticles must be stabilized so that they do not aggregate into larger particles in aqueous suspensions. Often surface modifiers such as surfactants are used to stabilize the nanoparticles, but such materials can have adverse physiological effects when administered in vivo. In addition, without a surface modifier present, the surface of the nanoparticles is unprotected, leading to a decrease in performance and stability.
In addition, it is often desirable to formulate nanoparticles as a dry material to improve patient compliance and facilitate incorporating the nanoparticles into a suitable dosage form. However, when liquids are removed from suspensions of nanoparticles, the nanoparticles often agglomerate or aggregate. When the resulting dry material is then administered to an aqueous solution (either in vitro or in vivo), large particles are formed, corresponding to the agglomerated or aggregated nanoparticles. These aggregates or agglomerated particles reduce the performance of the formulation.
Accordingly, there is a continuing need for nanoparticles that are stable, in the sense of not aggregating into larger particles, and that improve the bioavailability of active agents.